But hormonal therapy expressly for cardiac benefit still not recommended

Action Points

Note that this randomized trial found that hormone replacement therapy reduced carotid intima-media thickness among women who were in "early menopause" (less than 6 years past menopause).

Be aware that adverse events in the HRT group included one death from glioblastoma, 10 cases of breast cancer, one case of myocardial infarction, and three cases of deep vein thrombosis.

Oral estradiol therapy appeared to improved indications of cardiovascular disease in women in the early stages of menopause, a randomized trial found.

Age had a significant impact on the effects of estradiol, as women who were less than 6 years past menopause ("early menopause") experienced a lower rate of increase in carotid-artery intima-media thickness (CIMT) after 5 years of follow-up versus women who were classified as "late menopause" (P=0.007 for interaction), reported Howard N. Hodis, MD, of the University of Southern California in Los Angeles, and colleagues.

The early menopause group also had a statistically significant reduced rate of CIMT increase than women in the placebo group (0.0044 mm increase vs 0.0078 mm increase, respectively, P=0.008), they wrote in the New England Journal of Medicine.

These findings are in line with prior observational studies, which have shown inverse associations between postmenopausal hormone replacement therapy (HRT) and risk of cardiovascular disease. A subanalysis of the Women's Health Initiative (WHI) data 13 years later showed an age-related trend, where HRT was not associated with the same cardiovascular risk for women earlier in menopause compared with later in menopause.

Hodis and colleagues discussed a "timing hypothesis," which suggests HRT is associated with beneficial effects on atherosclerosis and coronary heart disease when women are first going through menopause, but not more than 10 years past menopause.

"Since the subanalysis of the WHI, there has been an appreciation that initiation of hormone therapy early after the menopause transition has a different impact than 10 years after," commented Lauren Streicher, MD, of Northwestern University in Chicago.

"There is relatively little information about the specifics of this 'critical window.' While the current recommendation is to offer hormone therapy for relief of symptoms only, this information builds the case that early initiation of therapy will have a positive impact on cardiovascular health," Streicher, who was not involved with the study, wrote in an email to MedPage Today.

Hodis and colleagues found no significant differences in the rates of carotid-artery intima-media thickness for women in the late menopause (≥10 years) group who were given estradiol versus placebo (P=0.29).

The Early versus Late Intervention Trial with Estradiol (ELITE) trial was comprised of 643 women stratified by age according to time since menopause. Each group was split into estradiol and placebo. The estradiol group received 1 mg of 17β estradiol, plus 45 mg progesterone vaginal gel for women with a uterus, while the control group received placebo pills and gel. Carotid-artery intima-media thickness was measured via cardiac CT every 6 months.

There were serious adverse events in 45 women in the placebo group and 43 in the estradiol group. The estradiol group had one death (from glioblastoma), 10 women with breast cancer, one woman with myocardial infarction, and three women with deep vein thrombosis, but the difference between the estradiol and placebo groups was not statistically significant, the authors reported.

Examining secondary outcomes, there were no significant differences between women in the estradiol group (either early or late menopause) and the placebo group for coronary atherosclerosis following their treatment regimen. However, measures of coronary atherosclerosis, such as coronary artery calcium scores, were much higher in the late menopause group compared to the early menopause group.

Judy Hannah, MD, of the National Institute on Aging in Bethesda, Md., which funded the study, said that there should now be less concern among clinicians about prescribing HRT to relieve menopausal symptoms in these younger women.

"A physician knows a patient and knows her risk factors -- whether she has a history of breast cancer, cardiovascular disease, or a history of smoking," she told MedPage Today. "But physicians should be more open to considering hormone replacement therapy, and whether it's an option for their patient."

But in an accompanying editorial, John F. Keaney Jr., MD, of University of Massachusetts Medical School in Worcester, and Caren G. Solomon, MD, of Brigham and Women's Hospital in Boston, said that the actual relevance of these results to clinical coronary heart disease remains questionable, in part due to the measures used.

"The trial assessed only surrogate measures of coronary heart disease and was not designed or powered to assess clinical events," Keaney and Solomon wrote. "The occurrence of myocardial infarction and stroke involves not only atherosclerotic plaque formation but also plaque rupture and thrombosis [and] any changes in these latter two phenomena would not be captured by the CIMT measurements."

Hodis' group acknowledged these limitations, and added that the sample size and duration of follow-up may have been insufficient to allow for the detection in between-group differences of coronary artery outcomes.

The editorialists also pointed out that the current clinical data that supports the timing hypothesis are "suggestive but inconsistent."

Finally, they said the trial results did not warrant straying from current clinical guidelines, which caution against using postmenopausal hormone therapy for the purpose of preventing cardiovascular events."

Hannah said it would be ideal to have a large database of women who were taking HRT hormone replacement therapy whose outcomes could be tracked. But she conceded that such an enterprise would require considerable resources.

"Electronic health records and large healthcare systems have the ability to mine data, so they may be able to gain some important information; they'll have how long the woman took the hormone therapy, the doses and type, and they may be able to see relationships between cardiovascular and other diseases and use of menopausal hormone products," she said. "But that would be a large database, and it would take a long time."

This study was supported by grants from the National Institute on Aging (NIA) and the NIH.

Hodis disclosed support from NIA. Co-authors disclosed relevant relationships with the NIH, GE, and TherapeuticsMD.

Keaney is associate editor of New England Journal of Medicine (NEJM). Solomon is a NEJM deputy editor.

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